Diabetes mellitus is a chronic condition resulting from insufficient β-cell mass, which leads to improper glycemia regulation. Research efforts have focused on expanding islets and β-cells in vitro for use in cell-based therapies to cure diabetes. Collagens are triple-helix extracellular matrix proteins with widespread expression in mammals. With multiple functions, collagen can provide structural integrity in addition to mediating cellular signaling. In the pancreas, collagens I and IV are abundant and support cell structures while also stimulating cell surface receptors to influence pancreatic cell processes. Collagen-based materials and scaffolds have also been used to assist in the maintenance and expansion of islet cells in vitro, primarily through integrin and discoindin domain receptors. Islet transplantation using collagen-based scaffolds may improve long-term glycemic control, but progressive research efforts are required to realize this potential in humans. This review will outline the critical role played by native collagens I and IV and their receptors in maintaining islet function. The advantages of using collagens I and IV as culture gels/scaffolds and islet encapsulation vehicles for transplantation will be described.